Disubstituted phenylpiperidines as modulators of dopamine and serotonin neurotransmission

Abstract

The present invention relates to compounds which have therapeutic effects against disorders in the central nervous system, and in particular new 4-(ortho,meta-disubstituted phenyl)-1-alkypiperidines. wherein R1, R2, and R3 are as defined.

1. A compound of Formula 1: 
       
         
           
           
               
               
           
         
         wherein: 
         R 1  is selected from the group consisting of —CN, —OCF 3 , —OCHF 2 , —SCF 3 , —SCHF 2 , —CF 3 , F, Cl, —CH 3  and —OCH 3 ; 
         R 2  is selected from the group consisting of F, Cl, Br, and CH 3 ; 
         R 3  is selected from the group consisting of C 1 -C 3  alkyls and allyl, 
         provided that when R 1  is CN or CF 3 , R 3  can only be C 1 -C 2  alkyls; 
         and the pharmaceutically acceptable salts thereof. 
       
     
     
       2. A compound according to  claim 1 , wherein R 1  is selected from the group consisting of, CN, CF 3 , Cl and F. 
     
     
       3. A compound according to  claim 1 , wherein R 1  is selected from the group consisting of F, C 1  and CF 3 . 
     
     
       4. A compound according to  claim 1 , wherein R 2  is selected from the group consisting of F and Cl. 
     
     
       5. A compound according to  claim 1 , wherein R 2  is F and R 3  is selected from the group consisting of n-propyl, and ethyl. 
     
     
       6. A compound according to  claim 1 , selected from the group consisting of
 4-(3-fluoro-2-methylphenyl)-1-propylpiperidine 
 1-ethyl-4-(3-fluoro-2-methylphenyl)piperidine 
 1-allyl-4-(3-fluoro-2-methylphenyl)piperidine 
 4-(2,3-difluorophenyl)-1-propylpiperidine 
 4-(2,3-difluorophenyl)-1-ethylpiperidine 
 1-allyl-4-(2,3-difluorophenyl)piperidine 
 4-(2-chloro-3-fluorophenyl)-1-propylpiperidine 
 4-(2-chloro-3-fluorophenyl)-1-ethylpiperidine 
 1-allyl-4-(2-chloro-3-fluorophenyl)piperidine 
 1-ethyl-4-[2-methyl-3-(trifluoromethyl)phenyl]piperidine 
 1-ethyl-4-[2-fluoro-3-(trifluoromethyl)phenyl]piperidine 
 4-[2-chloro-3-(trifluoromethyl)phenyl]-1-ethylpiperidine 
 4-(3-chloro-2-methylphenyl)-1-propylpiperidine 
 4-(3-chloro-2-methylphenyl)-1-ethylpiperidine 
 1-allyl-4-(3-chloro-2-methylphenyl)piperidine 
 4-(3-chloro-2-fluorophenyl)-1-propylpiperidine 
 4-(3-chloro-2-fluorophenyl)-1-ethylpiperidine 
 1-allyl-4-(3-chloro-2-fluorophenyl)piperidine 
 4-(2,3-dichlorophenyl)-1-propylpiperidine 
 4-(2,3-dichlorophenyl)-1-ethylpiperidine 
 1-allyl-4-(2,3-dichlorophenyl)piperidine 
 4-[3-(difluoromethoxy)-2-methylphenyl]-1-propylpiperidine 
 4-[3-(difluoromethoxy)-2-methylphenyl]-1-ethylpiperidine 
 1-allyl-4-[3-(difluoromethoxy)-2-methylphenyl]piperidine 
 4-[3-(difluoromethoxy)-2-fluorophenyl]-1-propylpiperidine 
 4-[3-(difluoromethoxy)-2-fluorophenyl]-1-ethylpiperidine 
 1-allyl-4-[3-(difluoromethoxy)-2-fluorophenyl]piperidine 
 4-[2-chloro-3-(difluoromethoxy)phenyl]-1-propylpiperidine 
 4-[2-chloro-3-(difluoromethoxy)phenyl]-1-ethylpiperidine 
 1-allyl-4-[2-chloro-3-(difluoromethoxy)phenyl]piperidine 
 4-[2-methyl-3-(trifluoromethoxy)phenyl]-1-propylpiperidine 
 1-ethyl-4-[2-methyl-3-(trifluoromethoxy)phenyl]piperidine 
 1-allyl-4-[2-methyl-3-(trifluoromethoxy)phenyl]piperidine 
 4-[2-fluoro-3-(trifluoromethoxy)phenyl]-1-propylpiperidine 
 1-ethyl-4-[2-fluoro-3-(trifluoromethoxy)phenyl]piperidine 
 1-allyl-4-[2-fluoro-3-(trifluoromethoxy)phenyl]piperidine 
 4-[2-chloro-3-(trifluoromethoxy)phenyl]-1-propylpiperidine 
 4-[2-chloro-3-(trifluoromethoxy)phenyl]-1-ethylpiperidine 
 1-allyl-4-[2-chloro-3-(trifluoromethoxy)phenyl]piperidine 
 3-(1-ethylpiperidin-4-yl)-2-methylbenzonitrile 
 3-(1-ethylpiperidin-4-yl)-2-fluorobenzonitrile 
 2-chloro-3-(1-ethylpiperidin-4-yl)benzonitrile 
 4-[2-fluoro-3-(trifluoromethyl)phenyl]-1-methylpiperidine 
 2-chloro-3-(1-methylpiperidin-4-yl)benzonitrile 
 4-[2-chloro-3-(trifluoromethyl)phenyl]-1-methylpiperidine 
 2-fluoro-3-(1-methylpiperidin-4-yl)benzonitrile. 
 
     
     
       7. A compound according to  claim 1 , selected from the group consisting of
 4-(2,3-difluorophenyl)-1-propylpiperidine 
 4-(2,3-difluorophenyl)-1-ethylpiperidine 
 1-allyl-4-(2,3-difluorophenyl)piperidine 
 4-(2-chloro-3-fluorophenyl)-1-propylpiperidine 
 4-(2-chloro-3-fluorophenyl)-1-ethylpiperidine 
 1-allyl-4-(2-chloro-3-fluorophenyl)piperidine 
 4-[2-chloro-3-(trifluoromethyl)phenyl]-1-ethylpiperidine 
 4-(3-chloro-2-fluorophenyl)-1-propylpiperidine 
 4-(3-chloro-2-fluorophenyl)-1-ethylpiperidine 
 1-allyl-4-(3-chloro-2-fluorophenyl)piperidine 
 4-(2,3-dichlorophenyl)-1-propylpiperidine 
 4-(2,3-dichlorophenyl)-1-ethylpiperidine 
 1-allyl-4-(2,3-dichlorophenyl)piperidine 
 4-[3-(difluoromethoxy)-2-fluorophenyl]-1-propylpiperidine 
 4-[3-(difluoromethoxy)-2-fluorophenyl]-1-ethylpiperidine 
 1-allyl-4-[3-(difluoromethoxy)-2-fluorophenyl]piperidine 
 4-[2-chloro-3-(difluoromethoxy)phenyl]-1-propylpiperidine 
 4-[2-chloro-3-(difluoromethoxy)phenyl]-1-ethylpiperidine 
 1-allyl-4-[2-chloro-3-(difluoromethoxy)phenyl]piperidine 
 4-[2-fluoro-3-(trifluoromethoxy)phenyl]-1-propylpiperidine 
 1-ethyl-4-[2-fluoro-3-(trifluoromethoxy)phenyl]piperidine 
 1-allyl-4-[2-fluoro-3-(trifluoromethoxy)phenyl]piperidine 
 4-[2-chloro-3-(trifluoromethoxy)phenyl]-1-propylpiperidine 
 4-[2-chloro-3-(trifluoromethoxy)phenyl]-1-ethylpiperidine 
 1-allyl-4-[2-chloro-3-(trifluoromethoxy)phenyl]piperidine 
 3-(1-ethylpiperidin-4-yl)-2-fluorobenzonitrile 
 2-chloro-3-(1-ethylpiperidin-4-yl)benzonitrile 
 4-[2-fluoro-3-(trifluoromethyl)phenyl]-1-methylpiperidine 
 2-chloro-3-(1-methylpiperidin-4-yl)benzonitrile 
 4-[2-chloro-3-(trifluoromethyl)phenyl]-1-methylpiperidine 
 2-fluoro-3-(1-methylpiperidin-4-yl)benzonitrile. 
 
     
     
       8. A pharmaceutical composition comprising a compound according to  claim 1  and one or more pharmaceutically acceptable carriers or diluents.